Temporal lobe epilepsy is a common and devastating neurological disorder that is often resistant to treatment. Although spontaneous epileptic seizures are believed to arise from an altered circuit within the temporal lobe, the nature of the causal network defect remains unidentified. The proposed experimental studies have been designed to elucidate the normal functional and structural organization of the hippocampus, with particular emphasis on the lamellar organization of this epileptogenic brain region. One hypothesis suggests that hippocampal segments are functionally separated from adjacent segments by translamellar inhibitory mechanisms, and that the breakdown of inhibitory barriers causes the formation of hyperexcitable "supersegments." This hypothesis will be addressed in a series of studies designed to demonstrate translamellar inhibition electrophysiologically, to identify the neurons that form the longitudinal projections that establish and maintain translamellar inhibition, and to determine whether loss of vulnerable interneurons causes translamellar disinhibition. Other studies will address the role of septal neurons in establishing lamellar hippocampal function. A second hypothesis predicts that synaptic reorganization forms abnormal connections between normally unconnected excitatory hippocampal neurons and that these interconnections give rise to hippocampal seizure discharges. A series of parallel electrophysiological studies in awake, chronically implanted animals will describe for the first time whether spontaneous epileptic seizures arise from the hippocampus, and will utilize a molecular marker of excitation to identify the neurons that are discharging in the most commonly used epilepsy models. Continuous electrophysiological monitoring will also determine the behavior of hippocampal neuron populations before and after injury, before and after injury-induced synaptic reorganization, and before and after the development of spontaneous seizures. New preliminary data indicating that human patients may have a pre-existing region of focal disinhibition will be used to develop several new models of temporal lobe epilepsy. These studies, which utilize a newly developed neurotoxin that selectively removes inhibitory interneurons in a highly focal region, will address the possibility that new animal models that may more closely approximate the human condition may be useful for detecting new pharmacological treatments for what remains a frequently drug-resistant neurological disorder.